Intraocular inflammation, commonly referred to as uveitis, is a leading cause of blindness from retinal photoreceptor cell apoptosis. A robust animal model of uveitis that closely resembles human uveitis is experimental autoimmune uveoretinitis (EAU). It is characterized by two phases: the early phase, 5-7 days postimmunization (p.i.) with an uveitogenic antigen, and the late/amplification phase, 12-14 days p.i. During the late phase, macrophages/neutrophils infiltrate the retina, and photoreceptor damage is noted histologically. The early phase, preceding the leukocyte infiltration, reveals Th1- and Th17-driven cytokines in the retina, nitration of cytochrome c (cyto c) in the photoreceptors from mitochondrial oxidative stress, and the release of nitrated cyto c into the cytosol. Such cyto c release is known to cause apoptosis. However, apoptosis is not a feature of early EAU, suggesting the presence of a protective mechanism(s) in the EAU retina that prevents photoreceptor apoptosis. Current preliminary studies suggest that the protection is offered by 1A crystallin upregulation and that this is unique to the photoreceptors and are not mediated by well-recognized anti-apoptotic proteins, including 1B crystallin, heat shock protein 27 and other heat shock proteins. Significantly, 1A crystallin knockout mice with early EAU show prominent apoptosis in the retina;such apoptosis is totally absent in the wild type mice with EAU. The data reveal the significance of 1A crystallin in preventing apoptosis in the retina. Moreover, it indicates that unlike other tissues, the photoreceptors utilize 1A crystallins selectively in the prevention of oxidative stress-mediated damage in early EAU, a novel protective mechanism observed in the photoreceptors. Based on our preliminary studies we hypothesize that 1) upregulation of 1A crystallin is a feature of the photoreceptors in response to mitochondrial oxidative stress;2) upregulated 1A crystallin interacts with the oxidative stress-induced nitrated cyto c, blocking the activation of caspases, and preventing apoptosis of photoreceptors. These hypotheses will be tested by three specific aims: 1) Determine the immune mechanism of 1A crystallin upregulation in the retina during EAU;2) Determine prevention of photoreceptor apoptosis by 1A crystallin in EAU and 3) Determine photoreceptor oxidative stress induction by iNOS in EAU. In-depth analysis of the immune mechanism(s) of 1A crystallin upregulation in EAU and its protective anti- apoptotic function will enhance our understanding, by clarifying the importance of crystallin upregulation in photoreceptor protection not only in uveitis, but in other oxidative stress-mediated retinal degenerations as well. Moreover the current proposal suggests that 1A crystallin can be a promising therapeutic agent for preventing oxidative stress-mediated photoreceptor damage. Such oxidative damage has been implicated in various blinding diseases, including age-related macular degeneration, retinal vein occlusion, and glaucoma.

Public Health Relevance

AlphaA crystallin is a unique protein present in the eye and other tissues. Lack of this protein can cause blindness, and supplement of this protein can prevent several blinding diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Anterior Eye Disease Study Section (AED)
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Mckie, George Ann
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Doheny Eye Institute
Los Angeles
United States
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Chan, Anita S Y; Saraswathy, Sindhu; Rehak, Matus et al. (2012) Neuroglobin protection in retinal ischemia. Invest Ophthalmol Vis Sci 53:704-11
Kaneko, Yutaka; Rao, Narsing A (2012) Mitochondrial oxidative stress initiates visual loss in sympathetic ophthalmia. Jpn J Ophthalmol 56:191-7
Wu, Guey Shuang; Jiang, Meisheng; Liu, Yi-Hsin et al. (2012) Phenotype of transgenic mice overexpressed with inducible nitric oxide synthase in the retina. PLoS One 7:e43089
Kase, Satoru; Meghpara, Beeran B; Ishida, Susumu et al. (2012) Expression of ?-crystallin in the retina of human sympathetic ophthalmia. Mol Med Rep 5:395-9
Saraswathy, Sindhu; Rao, Narsing A (2011) Posttranslational modification of differentially expressed mitochondrial proteins in the retina during early experimental autoimmune uveitis. Mol Vis 17:1814-21
Ko, MinHee K; Saraswathy, Sindhu; Parikh, Jignesh G et al. (2011) The role of TLR4 activation in photoreceptor mitochondrial oxidative stress. Invest Ophthalmol Vis Sci 52:5824-35
Saraswathy, Sindhu; Nguyen, Angeline M; Rao, Narsing A (2010) The role of TLR4 in photoreceptor {alpha}a crystallin upregulation during early experimental autoimmune uveitis. Invest Ophthalmol Vis Sci 51:3680-6
Saraswathy, Sindhu; Rao, Narsing A (2009) Mitochondrial proteomics in experimental autoimmune uveitis oxidative stress. Invest Ophthalmol Vis Sci 50:5559-66
Rigas, Panayota K; Kase, Satoru; Rao, Narsing A (2009) Expression of alpha-crystallins in human sebaceous carcinoma of the eyelid. Eur J Ophthalmol 19:702-7
Kase, S; Parikh, J G; Rao, N A (2009) Expression of heat shock protein 27 and alpha-crystallins in human retinoblastoma after chemoreduction. Br J Ophthalmol 93:541-4

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